Clinical activity of pan-RAF inhibitor tovorafenib in the registrational pediatric low-grade glioma arm of the phase 2 FIREFLY-1 (PNOC026) study.
Authors: Lindsay Baker Kilburn, Dong-Anh Khuong-Quang, Karsten Nysom, Daniel B Landi, David Simon Ziegler, Pablo Hernáiz Driever, Sarah Leary, Simon Bailey, Jasper van der Lugt, Sébastien Perreault, Angela Jae Waanders, Patricia Ann Baxter, Olaf Witt, Darren R. Hargrave, Geoffrey Brian McCowage, Xin Zhao, Daniel Da Costa, Michael Craig Cox, Peter Manley, Jordan Hansford
Journal: Journal of Clinical Oncology (2023)

10004 Background: Pediatric low-grade gliomas (LGGs) are the most common brain tumors of childhood. Genomic alterations of BRAF ( KIAA1549-BRAF fusions, 50–60% and BRAF V600E mutations, 5–15%) are the most frequent oncogenic drivers in pLGGs. Tovorafenib is an investigational, oral, selective, brain-penetrant, small molecule, type II pan-RAF inhibitor. Tovorafenib has demonstrated clinically meaningful responses in 24/35 patients (2 CR, 7 PR and 15 SD) in the pediatric phase 1B PNOC014 (NCT03429803) trial in patients with RAF-altered cancers (Wright, SNO 2022). Methods: FIREFLY-1 (NCT04775485) is a multicenter phase 2 study evaluating the efficacy and safety of tovorafenib monotherapy in patients with BRAF-altered cancers. Registrational arm 1 of FIREFLY-1 includes patients 6 months–25 years of age with recurrent or progressive LGG previously treated with ≥1 prior line of systemic therapy. Tovorafenib 420 mg/m 2 (not to exceed 600 mg) is administered weekly, in 28-day cycles, (tablet or liquid suspension formulation) until progression. The primary endpoint of arm 1 is ORR, as defined by Response Assessment in Neuro-Oncology (RANO) criteria and determined by blinded independent review. Results: As of September 28, 2022, arm 1 had enrolled 77 patients and is fully accrued. All patients had ≥6 months of follow-up. Median age at enrollment was 8 years (range 2–21). Patients were pretreated with a median of 3 prior lines of systemic therapy (range: 1–9); 60% had received prior MAPK pathway-targeted agents. The most common tumor site was optic pathway (51%). Sixty-four patients harbored a BRAF fusion/rearrangement (83%) in their tumors, and 13 (17%) had a BRAF V600E mutation. Median duration of tovorafenib treatment is 8.4 months (range 0.7–16.8), with 59 patients (77%) remaining on treatment at the time of data cutoff. Per independent assessment in 69 RANO-evaluable patients, ORR was 64%, [3 CR, 41 PR (10 unconfirmed) and 19 SD] with a clinical benefit rate of 91%. Responses were achieved in tumors with BRAF fusions and V600E mutations, including those previously treated with MAPK inhibitors. The most common treatment-related adverse events (TRAEs) of any grade were hair color changes (75%), increased creatine phosphokinase (64%), anemia (46%), fatigue (42%) and maculopapular rash (42%). Tovorafenib dose modifications occurred in 16 (21%) and discontinuations in 2 (3%) patients due to TRAEs. Updates from a longer follow-up on the 77 patients in arm 1 will be presented at the meeting. Conclusions: Tovorafenib was generally well tolerated and showed encouraging evidence of antitumor activity in children and young adults with recurrent/progressive BRAF-altered pLGG. LOGGIC/FIREFLY-2 (NCT05566795), a global, phase 3 trial is evaluating once-weekly tovorafenib monotherapy in newly-diagnosed patients with pLGG harboring a known activating RAF alteration. Clinical trial information: NCT04775485 .